Dimethylane-reserpine



United States Pate 2,872,377 DIMETHYLANE-RESERPINE Jay Morton Beiler, Wyndmoor, and Gustav .l. Martin,

Philadelphia, Pa., assignors to The National Drug Company, Philadelphia, Pa, a corporation of Delaware No Drawing. Application August 24, 1956 Serial No. 605,956

3 Claims. (Cl. 167-67) This invention relates to and has for its object the provision of compositions (and methods of preparing them) which are extremely effective as central nervous system depressants. The compositions of the invention comprise combinations of rauwolfia. (or reserpine) with certain pharmacologically active dioxolanes. They exert their effects at various levels in the nervous system, to yield advantages clearly unexpected from a consideration of the properties of the individual components.

Central nervous system depressants have been known and used medicinally for many years to induce sleep if pain is absent or to control convulsions. Probably the best known compounds of this type are the barbiturates which exert their effect on the higher centers of the brain. Obviously, therefore, their use substantially affects mental acuity. More recently, a group of compounds have become popular for use as depressants because of their effect at lower levels of the central nervous system. This class of medicinals, broadly described as tranquilizing agents, includes substances such as promazine, chlorpromazine and rauwolfia (or reserpine). The members of the group are believed to act on the hypothalamus without modifying mental acuity and, therefore, have been widely used in cases of psychological abnormality. Certain dioxolanes, especially 'dimethylane, have also become well 1 known because of the fact that they act as central nervous system depressants at a site even lower in the spinal cord. These compounds act on the spinal interneuro-ns, inhibiting the transmission of impulses along the lower part of the spinal cord; thus, they function as relaxants and are useful for the alleviation of tension symptoms.

In the present invention, where rauwolfia (or reserpine) is used in combination with a dioxolane, a marked potentiation of action is obtained. The duration of effect is significantly increased permitting the utilization of lower dosages than have been required heretofore. The invention also enables one to obtain the desired effect with a reduction in the side effects observed in using the prior art medicinals.

Rauwolfia extract is a dried extract of plants of the rauwolfia. family, especially Rauwolfia serpentina. The alkaloid content of the extract is usually about 30% by weight. However, the amount of alkaloids in the extract is not uniform and may vary substantially. The preferred active CNS-depressant alkaloid in the extract is reserpine and eitherthe reserpine or the parent rauwolfia may be used in the present invention. vVery recently, methods have been published for the synthesis of reserpine and the product produced in this manner, if it is economically feasible, may also be used. In the invention, it is preferred to use reserpine over the parent rauwolfia.

The dioxolane component of the present invention is a 2,2 dialiphatic 4 hydroxymethyl 1,3 dioxolane, particularly one in which the alkyl groups in the 2-position are lower alkyl and contain a total of 6-10 carbon atoms, especially 2,2-diisopropyl-4-hydroxymethyl-1,3-dioxolane (Dimethylane). Other useful 2,2-di-lower alkyl-4-hydroxymethyl-1,3-dioxolanes include those in which the 2,2-

, 2,872,377 Patented Feb. 3, 1959 ice ethel nonyl; methyl heptyl; etc. Pharmacologically active" dioxolanes such as 2-methyl-2-(1'-hydroxymethylamyl)- 1,3-dioxolane may also be used. In addition, the pharmacologically active alpha-glyceryl ethers, particularly 0- toloxy-l,Z-propanediol, may be employed as the second component.

As part of an in vivo test program it has been found that, although administration of 500 gamma/kg. reserpine gives no effect and the administration of 400 mg./kg. Dimethylane results in a loss of the righting reflex for 25 minutes, use of the combination results in loss of the righting reflex for about 40 minutes. Similar tests on dogs have shown that although 20 gamma per kg. reserpine yields some sedation and 200 mg. per kg. Dimethylane causes marked depression and apathy for about 20 minutes, use of the combination yields marked depression and apathy for about 90 minutes.

The compositions of the invention are preferably administered orally and any of the other well known dosage unit forms for such administration may be used. Thus, the compositions may be prepared for administration in the form of capsules, suspensions, elixirs, etc. Preferably, each dosage unit may contain about 250 mg. dioxolane component and about 0.25 mg. reserpine; and from about 3 to 6 such dosage units are usually administered daily. However, it is possible to use larger or smaller amounts per dosage unit with the ranges being preferably approximately 250-1500 mg. dioxolane to 0.1 to 1.0 mg. reserpine. The compositions may be prepared for administration in the form of capsules by dissolving or suspending the desired amount of reserpine (e. g. .25 mg. reserpine) in the desired amount of dioxolane (e. g. 250 mg. Dimethylane) with the aid of heat, then filling a soft gelatin capsule with the mixture.

The capsules, prepared as described above, may be enteric coated; and this enteric coated unit dosage form represents the most preferred aspect of the invention. More specifically, th'e capsules may be provided with an external coating of a cellulosic derivative which contains free carboxyl groups. The procedure for preparing such enteric coated products and the materials which may be used therefor are described in U. S. Patent No. 2,196,768. Any. of the procedures or materials used therein are applicable for use in the present invention. However, applicants prefer to use, as the cellulosic derivative capable of forming an enteric coating, (1) cellulose or regenerated cellulose esterified with one or more polycarboxylic acid, and (2) mixed esters or ether-esters, prepared for example, by reacting cellulose acetate, cellulose propionate, cellulose acetate-butyrate, ethyl cellulose, butyl cellulose, etc., with phthalic or maleic anhydrides or the like. Especially preferred as the coating material is a cellulose acetatephthalate, particularly one of those disclosed in Examples L VII and VIII of the aforementioned patent.

A specific example showing the preparation of the capsule of the invention has been described above. The description following shows how such capsule may be enteric coated to provide the preferred embodiment of the invention. The soft gelatin capsules which have been prepared in the usual manner in two sections to contain .25 mg. reserpine and 2.50 mg. Dimethylane are fitted together and each capsule is coated with a 4:1 dope (solvent; solids by weight), the solids component being a cellulose acetate phthalate containing 35% by weight phthalyl groups and prepared from cellulose acetate containing 33% acetyl; and the solvent is a mixture containing 4 parts ethylene chloride and 1 part methyl alcohol by weight. The solvent is allowed to evaporate to obtain the final product,

Suspensions and elixirsmay be prepared in the usual manner by solution or suspension in an alcoholic or aqueous medium to desirably contain .25 mg. reserpine and 250 mg. Dimethylane per ml. (teaspoonful). These liquid-containing forms of the medicinal compositions may obviously contain flavoring materials and other desirable additives. More specifically, an aqueous suspension may be prepared as follows: About 50 mg. reserpine is dissolved in 50 g. Dimethylane with. the aid of heat, the mixture is cooled and peanut oil is added to attain a volume of 400 ml. Sufficient distilled water is then added to obtain a final volume of 1000 ml. and, after adding 50 g. powdered acacia, emulsification is effected by stirring. If desired, one may add to the distilled water coloring matter (e. g. amaranth), sweeteners (e. g. simple syrup, saccharin, soluble saccharin, etc.), flavoring agents (e. g. oil of orange), preservatives (e. g. a mixture of methyl (0.09) and propyl (0.01) parasepts totalling one-tenth percent by weight of the composition), and an antioxidant (e. g. ethyl hydrocaffeate, .0l% by weight of the composition). The final emulsion contains 0.25 mg. reserpine and .25 g. Dimethylane per teaspoonful.

Similarly, an elixir may be prepared by dissolving 50 mg reserpine in 50 g.. Dimethylane with the aid of heat, cooling and adding to the mixture, 200-m1. ethanol, 500

4 ml. glycerol and sufficient distilled water to attain a final volume of 1000 ml. Coloring agents (such as amaranth), and flavoring materials (such as oil of orange, lemon and/ or lime) may be added if desired. The elixir contains .25 mg. reserpine and .25 g. Dirnethylane per teaspoonful.

This invention may be variously otherwise embodied within the scope of the appended claims.

We claim:

1. A composition comprising (1) 0.1-1.0 mg. reserpine and (2) 250-1500 mg. of 2,2-diisopropyl-4-hydroxymethyl-1,3-dioxolane.

2. An enteric coated capsule containing the composition of claim 1.

3. A unit dosage comprising 0.25 mg. reserpine and 250 mg. 2,2-diisopropyl-4-hydroxymethyl-1,3-dioxolane.

Modern Drug Encyclopedia, 6th ed., 1955, p. 337. A. M. and C. T. (Antibiotic Med. and Clinical Therapy), 111:5, p. 345, October 1956. 

1. A COMPOEITION COMPRISING (1) 0.1-1,0 MG, RESERPINE AND (2) 250-1500 MG. OF 2,2-DIISOPROPYL-4-HYDROXYMETHYL-1,3-DIOXOLANE. 